Since its first identification, SARS-CoV-2 infection has spread rapidly across the globe. Although there are no confirmed treatment approaches for COVID-19, a combined approach by controlling viral replication and suppressing the cytokine storm is considered as an important therapeutic strategy for COVID-19. We herein present a patient on PD who became critically ill due to COVID-19 and was treated with several extracorporeal treatments including PE, PMX-DHP and CHDF to suppress the cytokine storm. Although the dysregulation of inflammatory cytokines could not be completely suppressed, these extracorporeal treatments were effective against ARDS and sHLH, suggesting the significance of extracorporeal treatments in suppressing cytokine storm in COVID-19.
Studies on patients with COVID-19 in China showed that a high viral load correlated with worse symptoms and that SARS-CoV-2 was detectable until death in non- survivors, highlighting the importance of controlling viral replication for the treatment of COVID-19. Regarding antiviral therapy, we failed to effectively reduce viral replication in the present patient. Antiviral drugs favipiravir could not be initiated at an early stage of treatment as they had not been approved in Japan at the time. Favipiravir was initiated on day 14 after admission, immediately after its approval for use in Japan. However, the persistent positivity of the sputum samples for SARS-CoV-2 throughout the course of treatment (Figure 5) indicated that the viral replication could not be completely suppressed by hydroxychloroquine and favipiravir. CHDF has been reported to adsorb several types of drugs including favipiravir [7] and might have reduced the antiviral activity of favipiravir. Therefore, appropriate drug doses, administration methods and drug monitoring should be considered more carefully in patients undergoing CHDF. Additionally, corticosteroids used for ARDS in the present patient might also have led to delayed viral clearance.
COVID-19 has been reported to arise from an inflammatory cytokine storm due to SARS-CoV-2 infection; therefore, suppression of the cytokine storm is a key approach for the treatment of patients with COVID-19. Extracorporeal treatment approaches have been used to remove inflammatory cytokines in patients with septic shock and ARDS, whereas several studies have reported the efficacy of PE, PMX-DHP and CHDF in patients with COVID-19 [8]. In the present case, three extracorporeal treatment approaches were utilised. As the patient was on PD due to ESRD, CHDF was started on day one and continued during the entire clinical course. The efficacy of CHDF is controversial, although it has been reported to be beneficial in patients with ARDS by reducing the levels of inflammatory cytokines [6]. Therefore, we performed PMX-DHP, which has also been demonstrated to adsorb various cytokines. CHDF and PMX-DHP increased the PaO2/FiO2 ratio (Figure 2) in the present patient, indicating their efficacy in ARDS caused by COVID-19. Several studies have revealed that IL-6 plays a key role in cytokine storm and that serum IL-6 levels correlate with the severity of COVID-19. In the present case, serum IL-6 levels decreased after the treatment initiation and remained low during the clinical course (Figure 2), suggesting the possibility that uninterrupted CHDF treatment might have at least suppressed the elevation of serum IL-6 levels.
sHLH is commonly reported in patients with severe COVID-19 [9]. Consistently, the present patient developed sHLH on day 11 after admission. We did not find evidence of other diseases that could cause inflammation, including bacterial, viral and fungal infections, suggesting that the cytokine storm caused by COVID-19 was not completely controlled. Effective treatment of sHLH requires aggressive immunosuppression with agents such as corticosteroids and cyclosporin to control the hyperinflammatory state. These immunosuppressive treatments were not used in the present patient as they could further delay viral clearance. Given that the cytokine storm causes sHLH, the PE initiated on day 17 to remove cytokines rapidly improved thrombocytopenia and hyperferritinemia (Figure 3), suggesting that PE was protective against sHLH. Taken together, the extracorporeal treatment approaches employed in the present patient were effective in the treatment of ARDS and sHLH by suppressing the cytokine storm caused by COVID-19.
In addition to the failure in the control of viral replication, abnormal immune response due to ESRD might also have contributed to the incomplete suppression of the cytokine storm by the extracorporeal treatment approaches utilised in the present case. Patients with ESRD exhibit dysfunction in a variety of immune cells [10]. CD8+ T cells play an important role in a variety of viral infections, including SAR2-CoV-2 infection. Loss of renal function has been reported to decrease both the total number and the composition of circulating CD8+ T cells, indicating that patients with ESRD have reduced ability to eliminate virus. Therefore, it remains possible that the number and function of the CD8+ T cells might have been insufficient to clear SARS-CoV-2 in the present patient.
B cells are another immune cell type that plays an important role in protection from viral infections by generating non-specific as well as virus-specific antibodies. Patients with common variable immunodeficiencies and defective antibody production have been reported to exhibit severe symptoms of COVID-19 [11]. The present patient showed a marked decrease in circulating CD19+ B cell numbers (<10% of normal range) which did not recover during the clinical course. Moreover, his serum IgG levels remained low despite the administration of intravenous immunoglobulin (Figure 6). Another report showed that early intravenous immunoglobulin administration was protective in critically ill patients with COVID-19 [12], suggesting that a low gamma globulin level in early-stage COVID-19 might correlate with worse outcomes. Given these reports, an abnormal humoral immunity might have exacerbated the clinical condition of the present patient. However, it remains unclear why serum immunoglobulin levels were already low at the time of admission. One potential explanation is that SARS- CoV-2 might have a direct effect on B cells. As an abnormal humoral immune response might have exacerbated the cytokine storm in the present patient, earlier initiation of extracorporeal treatment approaches might have been more effective suppressing the cytokine storm. Further studies are necessary to clarify this possibility.
The CT scan conducted on day 28 revealed subacute cerebral infarction. SARS- CoV-2 infection can cause hypercoagulability [13], and the serum D-dimer levels remained high during the clinical course despite the continuous administration of the anticoagulant nafamostat in the present patient (Figure 6). The uncontrolled cytokine storm and viral replication might have exacerbated the hypercoagulability, which might be an underlying cause of the fatal outcome in the present patient. In patients with high D-dimer levels despite anticoagulant therapy, attention should be paid to thrombosis.
In summary, we herein presented a patient on PD who became critically ill with COVID-19 and was treated with several extracorporeal treatment approaches including PE, PMX-DHP and CHDF. These extracorporeal treatments were somewhat effective in suppressing the cytokine storm; however, the patient eventually died of an uncontrolled immune response and hypercoagulability. The cytokine storm might not have been suppressed at all without extracorporeal treatments, highlighting their significance in suppressing the cytokine storm during COVID-19. In addition to treatments suppressing abnormal immune response caused by SARS-CoV-2 infection, timely initiation of extracorporeal treatment approaches may be beneficial in critical ill patients with COVID-19.